Is It MSA-C or SPG7? How to Spot the Difference in Late-Onset Cerebellar Ataxia
"Unraveling the complexities of ILOCAs: A deep dive into differentiating between Multiple System Atrophy of cerebellar type (MSA-C) and SPG7 mutations for accurate diagnosis and care."
The realm of neurological disorders presents numerous diagnostic puzzles, with idiopathic late-onset cerebellar ataxia (ILOCA) standing out as a particularly intricate one. First described by Harding, ILOCA refers to the gradual onset of cerebellar ataxia (CA) without a clear cause, typically emerging around age 50 and sometimes accompanied by other neurological features. The quest to pinpoint specific etiologies has revealed that ILOCA is not a single entity but likely encompasses various sporadic and genetic conditions.
As genetic understanding has expanded, certain conditions have been identified within the ILOCA umbrella, such as Friedreich's ataxia, spinocerebellar ataxias (SCAs), Fragile X premutation, Gordon Holmes syndrome, and SYNE1 mutations. However, a significant portion of late-onset CA cases remains idiopathic, with multiple system atrophy of cerebellar type (MSA-C) often considered the most frequent underlying cause.
This article sheds light on a specific case of a patient initially diagnosed with ILOCA, who was later found to have a mutation in the SPG7 gene, known for causing hereditary spastic paraplegia. This case report, combined with a review of existing literature, underscores the importance of considering SPG7 mutations as a potential cause of the MSA-C phenotype within ILOCA, emphasizing the need for accurate differentiation to guide appropriate management and treatment strategies.
SPG7’s Role in Cerebellar Ataxia
SPG7 was first linked to pure and complicated hereditary spastic paraplegia with cerebellar atrophy, and is now described as a frequent cause of undiagnosed cerebellar and spastic ataxia pmc.ncbi.nlm.nih.gov. In Europe and North America, SPG7-related ataxia, with or without spasticity, is reported to account for 5–10% of undiagnosed ataxia cases, while SPG7 is considered rare in Japan pmc.ncbi.nlm.nih.gov. A 2026 letter discusses additional people carrying a single SPG7 p.Ala510Val variant and describes observations that broaden the clinical discussion, but says these data do not establish a defined conclusion link.springer.com.
Clinical Assessment and Genetic Testing
Ataxias may result from hereditary or sporadic genetic variants that lead to degeneration involving the cerebellum, cerebellar pathways, and/or spinal cord ataxia.org. SPG7 can involve balance and coordination problems as well as leg spasms and weakness ataxia.org. Although both ataxia and spasticity are usually present in SPG7, ataxia without spasticity has also been documented, so the absence of spasticity does not by itself rule out SPG7 jstage.jst.go.jp.
Decoding the Symptoms: MSA-C vs. SPG7
To illustrate the diagnostic challenges, consider the case of a 68-year-old woman who developed progressive walking difficulties in her early fifties. She described her condition as feeling "drunk," experienced frequent backward falls, and felt stiff after standing for more than 15 minutes. Additionally, she reported dizziness upon sudden sitting or standing, as well as urinary urgency with occasional incontinence. Her medical history included hypertension and migraine, but there was no family history of neurological diseases.
- Brain Imaging: Brain MRI, conducted more than 10 years after the onset of symptoms, excluded cerebellar, pons, and basal ganglia abnormalities, except for some ill-defined signal changes potentially related to small vessel disease. Her DATscan, a test to assess dopamine transporter function, was normal.
- Initial Diagnosis: Based on the clinical presentation, a movement disorder expert diagnosed her with MSA-C. However, further investigations, including metabolic and autonomic studies, came back normal or negative.
- Genetic Testing: Subsequent next-generation sequencing (NGS) revealed a homozygous missense variant [c.1529C>T, p.(Ala510Val)] in exon 11 of the SPG7 gene.
Recent Ataxia Research
Springer’s spinocerebellar ataxia research page describes itself as a collection of recent and impactful research, discoveries, ideas, and methods link.springer.com. Nature’s topic page characterizes spinocerebellar ataxias as a group of genetic, progressive neurodegenerative disorders involving the spine and cerebellum that can affect balance, coordination, and speech nature.com. A June 2026 Nature Reviews Neurology review focuses on recessive ataxias associated with ganglionopathy or polyneuropathy, particularly Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, and vestibular involvement nature.com.
SPG7 Can Mimic MSA-C
The term idiopathic late-onset cerebellar ataxias describes patients, often starting around age 50, with slowly progressive cerebellar ataxia of unknown cause, sometimes accompanied by other neurological features ncbi.nlm.nih.gov. In one report, exome sequencing identified compound heterozygous SPG7 mutations in two people with undiagnosed ataxia; the mutations had not previously been considered likely because pyramidal signs were absent neurology.org. Together, these reports illustrate why SPG7 can remain a diagnostic consideration in late-onset ataxia even when the expected pyramidal signs are not evident.
The Takeaway: Why Accurate Diagnosis Matters
In conclusion, this case underscores the diagnostic challenges in differentiating between ILOCA, MSA-C, and SPG7-related conditions. While clinical features may initially suggest MSA-C, genetic testing is crucial for accurate diagnosis, especially in atypical cases. By recognizing SPG7 mutations as potential mimics of MSA-C, clinicians can ensure appropriate management and treatment strategies, ultimately improving patient outcomes and quality of life.
A Diagnosis That Emerged Over Time
In a reported case, the diagnostic work-up initially focused on cerebellar ataxia. Over the following months, the patient’s ataxic gait became more spastic, and whole-exome sequencing revealed SPG7 mutations, confirming hereditary spastic paraplegia karger.com. The case illustrates how evolving clinical features and genetic testing contributed to the diagnosis.
Symptoms and the Search for an Explanation
A case report described a man whose symptoms began at age 39 with severe autism-like changes in emotional connectedness, executive dysfunction, and ataxia; testing found compound heterozygous SPG7 variants A510V and 1552+1 G>T pmc.ncbi.nlm.nih.gov. Another report on heterozygous SPG7 p.A510V discusses the limited but growing evidence for a possible role in late-onset cerebellar ataxia without spasticity, and recommends considering SPG7 in sporadic ataxia even without a clear recessive inheritance pattern iris.uniroma1.it. A separate spinocerebellar ataxia type 7 case report says diagnosis relied on clinical history, neurological examination, imaging, and genetic profiling ijcasereportsandimages.com.